Abstract
To determine whether methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with pre-eclampsia susceptibility. Literature searches of the Pubmed, Embase, BIOSIS Previews and Web of Science were conducted to identify all eligible articles up to January 18th, 2013. The pooled odds ratios (ORs) with 95 % confidence intervals (CIs) of five genetic models were calculated by fixed-effects or random-effects model. Publication bias, subgroup analysis, meta-regression and sensitivity analysis were also performed. A number of 49 studies including 51 samples consisted of 18,009 subjects (6,238 patients and 11,771 controls) were finally included. MTHFR C677T allele (TT or CT) carriers were 1.12 times more likely to develop pre-eclampsia (95 % CI 1.04–1.21) compared with 677CC homozygous individuals. Similar results were obtained under other genetic models. Restricted to severe pre-eclampsia, there was an increased risk for 677TT homozygotes compared with 677CC homozygotes (OR 1.43; 95 % CI 1.12–1.83). Subgroup analysis revealed a significant positive association between the C677T polymorphism (TT or CT) and pre-eclampsia in Asians (OR 1.41; 95 % CI 1.11–1.79) and white population (OR 1.14; 95 % CI 1.03–1.25). Meta-regression showed that study population, blinded genotyping, matching of cases and controls were not substantial sources of heterogeneity. For the MTHFR A1298C, ORs for all genetic models yielded a null association. This meta-analysis suggests that the MTHFR 677T allele might be associated with increased pre-eclampsia risk in Asian and white ethnicity and the subgroup of severe pre-eclampsia, while no association is observed between the MTHFR A1298C polymorphism and pre-eclampsia.
Similar content being viewed by others
References
Milne F, Redman C, Walker J, Baker P, Bradley J, Cooper C, de Swiet M, Fletcher G, Jokinen M, Murphy D, Nelson-Piercy C, Osgood V, Robson S, Shennan A, Tuffnell A, Twaddle S, Waugh J (2005) The pre-eclampsia community guideline (PRECOG): how to screen for and detect onset of pre-eclampsia in the community. BMJ 330(7491):576–580
Bulletins–Obstetrics ACoP (2002) ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol 99(1):159–167
Duley L (2009) The global impact of pre-eclampsia and eclampsia. Semin Perinatol 33(3):130–137. doi:10.1053/j.semperi.2009.02.010
Bellamy L, Casas JP, Hingorani AD, Williams DJ (2007) Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 335(7627):974. doi:10.1136/bmj.39335.385301.BE
Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R (2010) Pre-eclampsia. Lancet 376(9741):631–644. doi:10.1016/s0140-6736(10)60279-6
Noris M, Perico N, Remuzzi G (2005) Mechanisms of disease: pre-eclampsia. Nat Clin Pract Nephrol 1(2):98–114. doi:10.1038/ncpneph0035 quiz 120
Bailey LB, Gregory JF 3rd (1999) Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr 129(5):919–922
Goyette P, Pai A, Milos R, Frosst P, Tran P, Chen Z, Chan M, Rozen R (1998) Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome 9(8):652–656
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113. doi:10.1038/ng0595-111
Fletcher O, Kessling AM (1998) MTHFR association with arteriosclerotic vascular disease? Hum Genet 103(1):11–21
van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62(5):1044–1051. doi:10.1086/301825
Patrick TE, Powers RW, Daftary AR, Ness RB, Roberts JM (2004) Homocysteine and folic acid are inversely related in black women with preeclampsia. Hypertension 43(6):1279–1282. doi:10.1161/01.HYP.0000126580.81230.da
Zhang XYSD, Sun J (2008) The relationship between plasma homocysteine and preeclampsia. J Perinat Med 114:245–248
Powers RW, Evans RW, Majors AK, Ojimba JI, Ness RB, Crombleholme WR, Roberts JM (1998) Plasma homocysteine concentration is increased in preeclampsia and is associated with evidence of endothelial activation. Am J Obstet Gynecol 179(6 Pt 1):1605–1611
Roberts JM, Taylor RN, Goldfien A (1991) Clinical and biochemical evidence of endothelial cell dysfunction in the pregnancy syndrome preeclampsia. Am J Hypertens 4(8):700–708
Vollset SE, Refsum H, Irgens LM, Emblem BM, Tverdal A, Gjessing HK, Monsen AL, Ueland PM (2000) Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the hordaland homocysteine study. Am J Clin Nutr 71(4):962–968
Mikael LG, Pancer J, Jiang X, Wu Q, Caudill M, Rozen R (2012) Low dietary folate and methylenetetrahydrofolate reductase deficiency may lead to pregnancy complications through modulation of apoai and ifn-gamma in spleen and placenta, and through reduction of methylation potential. Mol Nutr Food Res. doi:10.1002/mnfr.201200152
Zusterzeel PL, Visser W, Blom HJ, Peters WH, Heil SG, Steegers EA (2000) Methylenetetrahydrofolate reductase polymorphisms in preeclampsia and the HELLP syndrome. Hypertens Pregnancy 19(3):299–307
Kosmas IP, Tatsioni A, Ioannidis JP (2004) Association of C677T polymorphism in the methylenetetrahydrofolate reductase gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis. J Hypertens 22(9):1655–1662
Lin J, August P (2005) Genetic thrombophilias and preeclampsia: a meta-analysis. Obstet Gynecol 105(1):182–192. doi:10.1097/01.AOG.0000146250.85561.e9
Xia XP, Chang WW, Cao YX (2012) Meta-analysis of the methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to pre-eclampsia. Hypertens Res. doi:10.1038/hr.2012.117
Demir SC, Evruke C, Ozgunen T, Kadayifci O, Altintas U, Kokangul S (2006) The relationship between pregnancy induced hypertension and congenital thrombophilia. Saudi Med J 27(8):1161–1166
Stonek F, Hafner E, Philipp K, Hefler LA, Bentz EK, Tempfer CB (2007) Methylenetetrahydrofolate reductase C677T polymorphism and pregnancy complications. Obstet Gynecol 110(2 Pt 1):363–368. doi:10.1097/01.AOG.0000270122.13198.6f
Yoshida A, Miura K, Nakayama D, Masuzaki H (2008) Correlation between preeclampsia and prevalence of polymorphism of angiotensinogen, methyleneteterahydrofolate reductase and factor v, prothrombin genes among Japanese women. Acta Med Nagasak 53(2):37–41
Kahn SR, Platt R, McNamara H, Rozen R, Chen MF, Genest J Jr, Goulet L, Lydon J, Seguin L, Dassa C, Masse A, Asselin G, Benjamin A, Miner L, Ghanem A, Kramer MS (2009) Inherited thrombophilia and preeclampsia within a multicenter cohort: the Montreal preeclampsia study. Obstet Gynecol Surv 64(6):366–368
Mislanova C, Martsenyuk O, Huppertz B, Obolenskaya M (2011) Placental markers of folate-related metabolism in preeclampsia. Reproduction 142(3):467–476. doi:10.1530/rep-10-0484
Dissanayake VH, Sirisena ND, Weerasekera LY, Gammulla CG, Seneviratne HR, Jayasekara RW (2012) Candidate gene study of genetic thrombophilic polymorphisms in pre-eclampsia and recurrent pregnancy loss in Sinhalese women. J Obstet Gynaecol Res. doi:10.1111/j.1447-0756.2012.01846.x
Lykke JA, Bare LA, Olsen J, Lagier R, Arellano AR, Tong C, Paidas MJ, Langhoff-Roos J (2012) Thrombophilias and adverse pregnancy outcomes: results from the Danish national birth cohort. J Thromb Haemost 10(7):1320–1325. doi:10.1111/j.1538-7836.2012.04773.x
Li KZD, Xue Y, Sun Y, Chen L, Guo J, Zhang G, Li P (2000) The common C677T polymorphism in the methylenetetrahydrofolate reductase gene is associated with neural tube defects and preeclampsia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi = Zhonghua Yixue Yichuanxue Zazhi = Chinese. J Med Genet 17:76–78
Zhang ZHZR, Liu AM, Xu X, Liu ZH (2007) Study on eNOS gene and MTHFR gene polymorphisms in preeclampsia. J Birth Health Hered 15:21–23
Shen XNHY, Tang SH, Zhang CL, Chen WS (2009) The relationship between the polymorphism of MTHFR gene and pre-eclampsia. J Pract Obstet Gynecol 25:236–238
Prasmusinto D, Skrablin S, Hofstaetter C, Fimmers R, Van Der Ven K (2002) The methylenetetrahydrofolate reductase 677 C→T polymorphism and preeclampsia in two populations. Obstet Gynecol 99(6):1085–1092
Gray RD, Atkinson QD (2003) Language-tree divergence times support the Anatolian theory of Indo-European origin. Nature 426(6965):435–439. doi:10.1038/nature02029
Cavalli-Sforza LL, Feldman MW (2003) The application of molecular genetic approaches to the study of human evolution. Nat Genet 33(Suppl):266–275. doi:10.1038/ng1113
Nei M, Roychoudhury AK (1993) Evolutionary relationships of human populations on a global scale. Mol Biol Evol 10(5):927–943
Cavalli-Sforza LL, Piazza A, Menozzi P, Mountain J (1988) Reconstruction of human evolution: bringing together genetic, archaeological, and linguistic data. Proc Natl Acad Sci USA 85(16):6002–6006
Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P (2013) The Newcastle–Ottawa scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. http://www.medicine.mcgill.ca/rtamblyn/Readings/The%20Newcastle%20-%20Scale%20for%20assessing%20the%20quality%20of%20nonrandomised%20studies%20in%20meta-analyses.pdf. Accessed 13 Oct 2013
Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560. doi:10.1136/bmj.327.7414.557
Song F, Sheldon TA, Sutton AJ, Abrams KR, Jones DR (2001) Methods for exploring heterogeneity in meta-analysis. Eval Health Prof 24(2):126–151
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634
Salanti G, Amountza G, Ntzani EE, Ioannidis JP (2005) Hardy–Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power. EJHG 13(7):840–848
Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP (2006) Impact of violations and deviations in Hardy–Weinberg equilibrium on postulated gene-disease associations. Am J Epidemiol 163(4):300–309. doi:10.1093/aje/kwj046
Dalmaz CA, Santos KG, Botton MR, Tedoldi CL, Roisenberg I (2006) Relationship between polymorphisms in thrombophilic genes and preeclampsia in a Brazilian population. Blood Cells Mol Dis 37(2):107–110. doi:10.1016/j.bcmd.2006.07.005
Williams MA, Sanchez SE, Zhang C, Bazul V (2004) Methylenetetrahydrofolate reductase 677 C→T polymorphism and plasma folate in relation to pre-eclampsia risk among Peruvian women. J Matern Fetal Neonatal Med 15(5):337–344. doi:10.1080/14767050410001680037
Rajkovic A, Mahomed K, Rozen R, Malinow MR, King IB, Williams MA (2000) Methylenetetrahydrofolate reductase 677 C→T polymorphism, plasma folate, vitamin b(12) concentrations, and risk of preeclampsia among black African women from Zimbabwe. Mol Genet Metab 69(1):33–39. doi:10.1006/mgme.1999.2952
Dusse LM, Carvalho MG, Braganca WF, Paiva SG, Godoi LC, Guimaraes DA, Fernandes AP (2007) Inherited thrombophilias and pre-eclampsia in Brazilian women. Eur J Obstet Gynecol Reprod Biol 134(1):20–23. doi:10.1016/j.ejogrb.2006.09.006
Yilmaz H, Unlucerci Y, Gurdol F, Isbilen E, Isbir T (2004) Association of pre-eclampsia with hyperhomocysteinaemia and methylenetetrahydrofolate reductase gene C677T polymorphism in a Turkish population. Aust N Z J Obstet Gynaecol 44(5):423–427. doi:10.1111/j.1479-828X.2004.00283.x
O’Shaughnessy KM, Fu B, Ferraro F, Lewis I, Downing S, Morris NH (1999) Factor V Leiden and thermolabile methylenetetrahydrofolate reductase gene variants in an East Anglian preeclampsia cohort. Hypertension 33(6):1338–1341
De Maat MP, Jansen MW, Hille ET, Vos HL, Bloemenkamp KW, Buitendijk S, Helmerhorst FM, Wladimiroff JW, Bertina RM, De Groot CJ (2004) Preeclampsia and its interaction with common variants in thrombophilia genes. J Thromb Haemost 2(9):1588–1593. doi:10.1111/j.1538-7836.2004.00861.x
Rigo J Jr, Nagy B, Fintor L, Tanyi J, Beke A, Karadi I, Papp Z (2000) Maternal and neonatal outcome of preeclamptic pregnancies: the potential roles of Factor V Leiden mutation and 5,10-methylenetetrahydrofolate reductase. Hypertens Pregnancy 19(2):163–172
Morrison ER, Miedzybrodzka ZH, Campbell DM, Haites NE, Wilson BJ, Watson MS, Greaves M, Vickers MA (2002) Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review. Thromb Haemost 87(5):779–785
Grandone E, Margaglione M, Colaizzo D, Cappucci G, Paladini D, Martinelli P, Montanaro S, Pavone G, Di Minno G (1997) Factor V Leiden, C>T MTHFR polymorphism and genetic susceptibility to preeclampsia. Thromb Haemost 77(6):1052–1054
Pegoraro RJ, Chikosi A, Rom L, Roberts C, Moodley J (2004) Methylenetetrahydrofolate reductase gene polymorphisms in Black South Africans and the association with preeclampsia. Acta Obstet Gynecol Scand 83(5):449–454. doi:10.1111/j.0001-6349.2004.0355.x
Also-Rallo E, Lopez-Quesada E, Urreizti R, Vilaseca MA, Lailla JM, Balcells S, Grinberg D (2005) Polymorphisms of genes involved in homocysteine metabolism in preeclampsia and in uncomplicated pregnancies. Eur J Obstet Gynecol Reprod Biol 120(1):45–52. doi:10.1016/j.ejogrb.2004.08.008
Jaaskelainen E, Keski-Nisula L, Toivonen S, Romppanen EL, Helisalmi S, Punnonen K, Heinonen S (2006) MTHFR C677T polymorphism is not associated with placental abruption or preeclampsia in Finnish women. Hypertens Pregnancy 25(2):73–80. doi:10.1080/10641950600745137
Davalos IP, Moran MC, Martinez-Abundis E, Gonzalez-Ortiz M, Flores-Martinez SE, Machorro V, Sandoval L, Figuera LE, Mena JP, Oliva JM, Tlacuilo-Parra JA, Sanchez-Corona J, Salazar-Paramo M (2005) Methylenetetrahydrofolate reductase C677T polymorphism and Factor V Leiden variant in Mexican women with preeclampsia/eclampsia. Blood Cells Mol Dis 35(1):66–69. doi:10.1016/j.bcmd.2005.03.008
Powers RW, Minich LA, Lykins DL, Ness RB, Crombleholme WR, Roberts JM (1999) Methylenetetrahydrofolate reductase polymorphism, folate, and susceptibility to preeclampsia. J Soc Gynecol Investig 6(2):74–79
Livingston JC, Barton JR, Park V, Haddad B, Phillips O, Sibai BM (2001) Maternal and fetal inherited thrombophilias are not related to the development of severe preeclampsia. Am J Obstet Gynecol 185(1):153–157. doi:10.1067/mob.2001.114691
Kaiser T, Brennecke SP, Moses EK (2001) C677T methylenetetrahydrofolate reductase polymorphism is not a risk factor for pre-eclampsia/eclampsia among Australian women. Hum Hered 51(1–2):20–22
Perez-Mutul J, Gonzalez-Herrera L, Sosa-Cabrera T, Martinez-Olivares R (2004) A mutation in the 5,10-methylenetetrahydrofolate reductase gene is not associated with preeclampsia in women of Southeast Mexico. Arch Med Res 35(3):231–234. doi:10.1016/j.arcmed.2004.02.004
Kobashi G, Yamada H, Asano T, Nagano S, Hata A, Kishi R, Fujimoto S, Kondo K (2000) Absence of association between a common mutation in the methylenetetrahydrofolate reductase gene and preeclampsia in Japanese women. Am J Med Genet 93(2):122–125
Aggarwal S, Dimri N, Tandon I, Agarwal S (2011) Preeclampsia in north Indian women: the contribution of genetic polymorphisms. J Obstet Gynaecol Res 37(10):1335–1341. doi:10.1111/j.1447-0756.2010.01523.x
Laivuori H, Kaaja R, Ylikorkala O, Hiltunen T, Kontula K (2000) 677 C→T polymorphism of the methylenetetrahydrofolate reductase gene and preeclampsia. Obstet Gynecol 96(2):277–280
Kim YJ, Williamson RA, Murray JC, Andrews J, Pietscher JJ, Peraud PJ, Merrill DC (2001) Genetic susceptibility to preeclampsia: roles of cytosine-to-thymine substitution at nucleotide 677 of the gene for methylenetetrahydrofolate reductase, 68-base pair insertion at nucleotide 844 of the gene for cystathionine (beta)-synthase, and Factor V Leiden mutation. Am J Obstet Gynecol 184(6):1211–1217
Sohda S, Arinami T, Hamada H, Yamada N, Hamaguchi H, Kubo T (1997) Methylenetetrahydrofolate reductase polymorphism and pre-eclampsia. J Med Genet 34(6):525–526
Canto P, Canto-Cetina T, Juarez-Velazquez R, Rosas-Vargas H, Rangel-Villalobos H, Canizales-Quinteros S, Velazquez-Wong AC, Villarreal-Molina MT, Fernandez G, Coral-Vazquez R (2008) Methylenetetrahydrofolate reductase C677T and glutathione S-transferase P1 A313G are associated with a reduced risk of preeclampsia in Maya–Mestizo women. Hypertens Res 31(5):1015–1019. doi:10.1291/hypres.31.1015
Lachmeijer AM, Arngrimsson R, Bastiaans EJ, Pals G, ten Kate LP, de Vries JI, Kostense PJ, Aarnoudse JG, Dekker GA (2001) Mutations in the gene for methylenetetrahydrofolate reductase, homocysteine levels, and vitamin status in women with a history of preeclampsia. Am J Obstet Gynecol 184(3):394–402
Chikosi AB, Moodley J, Pegoraro RJ, Lanning PA, Rom L (1999) 5,10-Methylenetetrahydrofolate reductase polymorphism in Black South African women with pre-eclampsia. Br J Obstet Gynaecol 106(11):1219–1220. doi:10.1111/j.1471-0528.1999.tb08152.x
Muetze S, Leeners B, Ortlepp JR, Kuse S, Tag CG, Weiskirchen R, Gressner AM, Rudnik-Schoeneborn S, Zerres K, Rath W (2008) Maternal Factor V Leiden mutation is associated with HELLP syndrome in Caucasian women. Acta Obstet Gynecol Scand 87(6):635–642. doi:10.1080/00016340802112740
Nagy B, Hupuczi P, Papp Z (2007) High frequency of methylenetetrahydrofolate reductase 677TT genotype in Hungarian HELLP syndrome patients determined by quantitative real-time PCR. J Hum Hypertens 21(2):154–158. doi:10.1038/sj.jhh.1002122
Watanabe H, Hamada H, Yamakawa-Kobayashi K, Yoshikawa H, Arinami T (2001) Evidence for an association of the R485K polymorphism in the coagulation factor V gene with severe preeclampsia from screening 35 polymorphisms in 27 candidate genes. Thromb Haemost 86(6):1594–1595
Ibrahim ZM, Metawie MAE, El-Baz AM, El-Bahie MA (2011) Methylenetetrahydrofolate C677T polymorphism and pre-eclamptic Egyptian women. Middle East Fertil Soc J 17(2):105–110
Rahimi Z, Malek-Khosravi S, Rahimi Z, Jalilvand F, Parsian A (2012) MTHFR C677T and eNOS G894T variants in preeclamptic women: contribution to lipid peroxidation and oxidative stress. Clin Biochem 42(1–2):143–147
Dogan OO, Simsek Y, Celen S, Danisman N (2011) Frequency of hereditary thrombophilia, anticoagulant activity, and homocysteine levels in patients with hemolysis, elevated liver functions and low thrombocyte count (HELLP) syndrome. J Obstet Gynaecol Res 37(6):527–533. doi:10.1111/j.1447-0756.2010.01397.x
Fabbro D, D’Elia AV, Spizzo R, Driul L, Barillari G, Di Loreto C, Marchesoni D, Damante G (2003) Association between plasminogen activator inhibitor 1 gene polymorphisms and preeclampsia. Gynecol Obstet Invest 56(1):17–22. doi:10.1159/000072326
Gerhardt A, Goecke TW, Beckmann MW, Wagner KJ, Tutschek B, Willers R, Bender HG, Scharf RE, Zotz RB (2005) The G20210A prothrombin-gene mutation and the plasminogen activator inhibitor (PAI-1) 5G/5G genotype are associated with early onset of severe preeclampsia. J Thromb Haemost 3(4):686–691
Jarvenpaa J, Pakkila M, Savolainen ER, Perheentupa A, Jarvela I, Ryynanen M (2006) Evaluation of factor V Leiden, prothrombin and methylenetetrahydrofolate reductase gene mutations in patients with severe pregnancy complications in Northern Finland. Gynecol Obstet Invest 62(1):28–32. doi:10.1159/000091814
Klai S, Fekih-Mrissa N, El Housaini S, Kaabechi N, Nsiri B, Rachdi R, Gritli N (2011) Association of MTHFR A1298C polymorphism (but not of MTHFR C677T) with elevated homocysteine levels and placental vasculopathies. Blood Coagul Fibrinolysis 22(5):374–378. doi:10.1097/MBC.0b013e328344f80f
Levesque S, Moutquin JM, Lindsay C, Roy MC, Rousseau F (2004) Implication of an AGT haplotype in a multigene association study with pregnancy hypertension. Hypertension 43(1):71–78. doi:10.1161/01.hyp.0000104525.76016.77
Hiltunen LM, Laivuori H, Rautanen A, Kaaja R, Kere J, Krusius T, Paunio M, Rasi V (2009) Blood group AB and Factor V Leiden as risk factors for pre-eclampsia: a population-based nested case–control study. Thromb Res 124(2):167–173. doi:10.1016/j.thromres.2008.11.012
D’Elia AV, Driul L, Giacomello R, Colaone R, Fabbro D, Di Leonardo C, Florio P, Petraglia F, Marchesoni D, Damante G (2002) Frequency of factor V, prothrombin and methylenetetrahydrofolate reductase gene variants in preeclampsia. Gynecol Obstet Investig 53(2):84–87
Raijmakers MT, Zusterzeel PL, Steegers EA, Peters WH (2001) Hyperhomocysteinaemia: a risk factor for preeclampsia? Eur J Obstet Gynecol Reprod Biol 95(2):226–228
Staines-Urias E, Paez MC, Doyle P, Dudbridge F, Serrano NC, Ioannidis JP, Keating BJ, Hingorani AD, Casas JP (2012) Genetic association studies in pre-eclampsia: systematic meta-analyses and field synopsis. Int J Epidemiol 41(6):1764–1775. doi:10.1093/ije/dys162
Buurma AJ, Turner RJ, Driessen JH, Mooyaart AL, Schoones JW, Bruijn JA, Bloemenkamp KW, Dekkers OM, Baelde HJ (2013) Genetic variants in pre-eclampsia: a meta-analysis. Hum Reprod Update. doi:10.1093/humupd/dms060
Murphy RP, Donoghue C, Nallen RJ, D’Mello M, Regan C, Whitehead AS, Fitzgerald DJ (2000) Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol 20(1):266–270
Mendilcioglu I, Bilgen T, Arikan Y, Keser I, Simsek M, Timuragaoglu A (2011) The association between inherited thrombophilias and pregnancy-related hypertension recurrence. Arch Gynecol Obstet 284(4):837–841. doi:10.1007/s00404-010-1756-y
Pennington KA, Schlitt JM, Jackson DL, Schulz LC, Schust DJ (2012) Preeclampsia: multiple approaches for a multifactorial disease. Dis Model Mech 5(1):9–18. doi:10.1242/dmm.008516
Gifford RW, August PA, Cunningham G, Green LA, Lindheimer MD, McNellis D, Roberts JM, Sibai BM, Taler SJ (2000) Report of the national high blood pressure education program working group on high blood pressure in pregnancy. Am J Obstet Gynecol 183(1):S1–S22
Chelbi ST, Vaiman D (2008) Genetic and epigenetic factors contribute to the onset of preeclampsia. Mol Cell Endocrinol 282(1–2):120–129. doi:10.1016/j.mce.2007.11.022
Hill LD, York TP, Kusanovic JP, Gomez R, Eaves LJ, Romero R, Strauss JF 3rd (2011) Epistasis between COMT and MTHFR in maternal-fetal dyads increases risk for preeclampsia. PLoS ONE 6(1):e16681. doi:10.1371/journal.pone.0016681
Goddard KA, Tromp G, Romero R, Olson JM, Lu Q, Xu Z, Parimi N, Nien JK, Gomez R, Behnke E, Solari M, Espinoza J, Santolaya J, Chaiworapongsa T, Lenk GM, Volkenant K, Anant MK, Salisbury BA, Carr J, Lee MS, Vovis GF, Kuivaniemi H (2007) Candidate-gene association study of mothers with pre-eclampsia, and their infants, analyzing 775 SNPS in 190 genes. Hum Hered 63(1):1–16. doi:10.1159/000097926
Gopec Consortium (2005) Disentangling fetal and maternal susceptibility for pre-eclampsia: a British multicenter candidate-gene study. Am J Hum Genet 77(1):127–131. doi:10.1086/431245
McCarthy MI, Hirschhorn JN (2008) Genome-wide association studies: past, present and future. Hum Mol Genet 17(R2):R100–R101. doi:10.1093/hmg/ddn298
Lockwood C, Wendel G (2011) Practice bulletin no. 124: inherited thrombophilias in pregnancy. Obstet Gynecol 118(3):730–740. doi:10.1097/AOG.0b013e3182310c6f
Conflict of interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
Xing Li, Ya L. Luo have contributed equally to this work.
Rights and permissions
About this article
Cite this article
Li, X., Luo, Y.L., Zhang, Q.H. et al. Methylenetetrahydrofolate reductase gene C677T, A1298C polymorphisms and pre-eclampsia risk: a meta-analysis. Mol Biol Rep 41, 5435–5448 (2014). https://doi.org/10.1007/s11033-014-3415-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-014-3415-z